Wondergem R, Graves BM, Li C, Williams DL. Lipopolysaccharide prolongs action potential duration in HL-1 mouse cardiomyocytes. Am J Physiol Cell Physiol 303: C825-C833, 2012. First published August 15, 2012; doi:10.1152/ajpcell.00173.2012.-Sepsis has deleterious effects on cardiac function including reduced contractility. We have shown previously that lipopolysaccharides (LPS) directly affect HL-1 cardiac myocytes by inhibiting Ca 2ϩ regulation and by impairing pacemaker "funny" current, I f. We now explore further cellular mechanisms whereby LPS inhibits excitability in HL-1 cells. LPS (1 g/ml) derived from Salmonella enteritidis decreased rate of firing of spontaneous action potentials in HL-1 cells, and it increased their pacemaker potential durations and decreased their rates of depolarization, all measured by whole cell current clamp. LPS also increased action potential durations and decreased their amplitude in cells paced at 1 Hz with 0.1 nA, and 20 min were necessary for maximal effect. LPS decreased the amplitude of a rapidly inactivating inward current attributed to Na ϩ and of an outward current attributed to K ϩ ; both were measured by whole cell voltage clamp. The K ϩ currents displayed a resurgent outward tail current, which is characteristic of the rapid delayed-rectifier K ϩ current, IKr. LPS accordingly reduced outward currents measured with pipette Cs ϩ substituted for K ϩ to isolate IKr. E-4031 (1 M) markedly inhibited IKr in HL-1 cells and also increased action potential duration; however, the direct effects of E-4031 occurred minutes faster than the slow effects of LPS. We conclude that LPS increases action potential duration in HL-1 mouse cardiomyocytes by inhibition of IKr and decreases their rate of firing by inhibition of INa. This protracted time course points toward an intermediary metabolic event, which either decreases available mouse ether-a-go-go (mERG) and Na ϩ channels or potentiates their inactivation.delayed rectifier K ϩ current; patch-clamp electrophysiology; Salmonella enteritidis; E-4031 SEPSIS IS A COMPLEX CLINICAL problem that can progress into multiorgan dysfunction syndrome (MODS) and death. At least one-half of the high mortality rates of severe-sepsis, sepsis, and MODS result from cardiovascular failure (27). Approximately 40% of patients in septic shock also experience myocardial dysfunction (36, 44), which comprises reduced systolic contractility, impaired diastolic relaxation, and ventricular dilatation. The initial clinical pattern, however, ironically is termed "hyperdynamic," because it often presents with high cardiac output, elevated heart rate, and vasodilatation of the dermis (27). This is attributable in part to the volume loading that is frequently the initial treatment for septic shock patients to maintain cardiac output and organ perfusion (15, 28). As is often the case in the complexity of sepsis, the prevailing symptoms can mask organ and system failure occurring at a deeper level in the clinical spectrum.The most prevalent sign of myocardial depressio...